Manufacturers Face New Risk-Management Requirements

The abuse and misuse of opioid painkillers is out of control, and the US Food and Drug Administration wants to defuse this serious public-health crisis. Previous risk-mitigation programs have failed to halt the inappropriate use of these drugs, prompting FDA to put more teeth into oversight through the Risk Evaluation and Mitigation Strategies (REMS) program established by the FDA Amendments Act of 2007 (FDAAA). FDA has called on manufacturers and other interested parties to help devise a workable REMS that will ensure continued access to medications essential for patients suffering from chronic pain, but also curb inappropriate prescribing, unintentional overdosing, and intentional abuse.

The opioid REMS project reflects FDA's interest in building on the host of provisions in FDAAA designed to ensure drug safety through the entire product life cycle. In addition to the REMS program, the statute gives the agency the power to require postapproval label changes when new safety issues arise and to crack down on manufacturers that fail to conduct agreed-on postmarketing studies. FDAAA also requires companies to list extensive clinical trial information and study results on the ClinicalTrials.gov public website. The listing is another way to ensure that safety issues that arise during clinical research are fully disclosed to regulatory authorities and to the public.

Implementing the FDAAA REMS program has been complex and time-consuming because it has required FDA to assess and update existing risk-management programs for dozens of drugs, while also developing new policies to fit its enhanced authorities. In March 2008, FDA identified some 24 manufacturers with marketed drugs such as isotretinoin, thalidomide, mifepristone, alosetron, and clozapine, that already had risk-management plans in place and thus were deemed to have REMS.

Under FDAAA, REMS may consist of simply a Medication Guide and a timetable for evaluating the drug product after 18 months, three years, and seven years after approval. More elaborate REMS programs may require a communication plan for conveying safety information to prescribers, pharmacists, and patients through Dear Doctor letters and notices to professional societies, state licensing boards, and medical journals. Makers of the highest-risk drugs also have to establish Elements to Assure Safe Use, which can include special training or certification of healthcare providers and pharmacists, limited distribution programs to ensure that a drug is dispensed only to patients who meet certain criteria, patient monitoring to identify adverse reactions, and enrollment of patients in registries for long-term oversight. Most of the products deemed to have REMS already supported many of the REMS provisions, but manufacturers had to submit proposals describing how their programs fit new REMS requirements. During the past 18 months, FDA has approved REMS for approximately 50 products, including drugs already on the market as well as new treatments.